N-substituted azabicycloalkane derivatives, their preparation and use

ABSTRACT

Compounds of the formula I ##STR1## where B, R 1 , R 2 , n and A have the meanings given in the description, and their preparation are described. The novel compounds are suitable for the control of diseases.

The invention relates to novel N-substituted azabicycloalkanederivatives, their preparation and use for preparing pharmaceuticalactive compounds.

It has been disclosed that basically substituted butyrophenonederivatives or benzamide derivatives have neuroleptic orcerebro-protective activity (U.S. Pat. No. 4,605,655, EP 410 114, DE 1289 845, EP 400 661, DE 29 41 880, EP 190 472, DE 42 19 973).

The observed high affinities to dopamine and serotonin receptor subtypesappear to play a particular role in this context.

It has now been found that N-substituted 3-azabicycloalkane derivativesof the formula I ##STR2## where B is a 3-, 5- or 6-membered ring whichcan contain 1 nitrogen atom and/or 1 oxygen atom and possibly one doublebond,

R¹ is a phenyl group which is unsubstituted or mono- or disubstituted byhalogen atoms or C₁ -C₄ -alkyl, trifluoromethyl, hydroxyl, C₁ -C₄-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups,

R² is a hydrogen atom, a C₁ -C₄ -alkyl radical, or a phenyl group whichis unsubstituted or substituted by halogen, methoxy, hydroxyl or amino,

n is the number 0, 1, 2, 3 or 4,

A is a hydrogen atom or one of the radicals --CO--R⁵ or --NR⁶ --CO--R⁷,

R⁵ is a phenyl group which is unsubstituted or mono- or disubstituted byfluorine, chlorine, bromine or a hydroxyl, nitro, amino, C₁₋₄-alkanoylamino, C₁₋₄ -alkylamino, C₁ -C₄ -alkyl or methoxy group or anaphthyl group which is unsubstituted or substituted by fluorine orchlorine,

R⁶ is a hydrogen atom or a methyl group, and

R⁷ is a phenyl group which is mono- or disubstituted by fluorine,chlorine, bromine, C₁ -C₄ -alkyl, hydroxyl or methoxy or monosubstitutedby nitro, cyano, trifluoromethyl, amino, C₁ -C₄ -alkylamino or di-C₁ -C₄-alkylamino or a thienyl, naphthyl, benzothienyl or indenyl group whichis unsubstituted or substituted by fluorine, chlorine or nitro,

and their salts with physiologically tolerable acids, have usefulpharmacological properties.

In the formula I, the substituents R¹ to R⁶ and n preferably have thefollowing meanings:

R¹ : phenyl, unsubstituted or substituted by fluorine, chlorine,methoxy, trifluoromethyl, nitro, hydroxyl or amino,

R² : hydrogen, methyl,

n: 2 or 3,

R⁵ : p-fluorophenyl, phenyl, p-chlorophenyl, 1-naphthyl,

R⁶ : hydrogen,

R⁷ : phenyl, p-fluorophenyl, o-aminophenyl, o-N-methylaminophenyl,5-chlorothien-1-yl, 1-naphthyl, 3-indenyl, 3-chloro-1-benzothien-2-yl.

The bicyclic ring system in the left moiety of the formula I isparticularly ##STR3##

Preferred compounds are in particular those where

R¹ is phenyl which is preferably substituted in the p-position byfluorine or chlorine or in the m-position by fluorine or chlorine and

R² is hydrogen or methyl.

The compounds of the formula I according to the invention can beprepared by reacting a compound of the formula II

    Nu--(CH.sub.2).sub.n --A                                   II,

where A and n have the meanings given and Nu is a nucleofugic leavinggroup, with a 3-azabicycloalkane derivative of the formula III ##STR4##where B, R¹ and R² have the meaning given above, removing any protectivegroups present and if desired converting the compound thus obtained intothe acid addition salt of a physiologically tolerable acid.

Suitable nucleofugic leaving groups for Nu are preferably halogen atoms,in particular bromine or chlorine.

The reaction is expediently carried out in the presence of an inertbase, such as triethylamine or potassium carbonate, as acid acceptor inan inert solvent, such as a cyclic saturated ether, in particulartetrahydrofuran or dioxane, or a benzene hydrocarbon, such as toluene orxylene.

The reaction is in general carried out at from 20° to 150° C., inparticular from 80° to 140° C., and is in general complete within from 1to 10 hours.

The compounds of the formula I according to the invention can either bepurified by recrystallization from the customary organic solvents,preferably from a lower alcohol, such as ethanol, or by columnchromatography.

Racemates can be resolved into the enantiomers in a simple manner byclassical cleavage using optically active carboxylic acids, e.g.tartaric acid derivatives, in an inert solvent, e.g. lower alcohols.

The free 3-azabicycloalkane derivatives of the formula I can beconverted to the acid addition salt of a pharmacologically tolerableacid in a customary manner, preferably by treating a solution with anequivalent of the corresponding acid. Pharmaceutically tolerable acidsare, for example, hydrochloric acid, phosphoric acid, sulfuric acid,methanesulfonic acid, sulfamic acid, maleic acid, fumaric acid, oxalicacid, tartaric acid or citric acid.

The compounds according to the invention have useful pharmacologicalproperties. They can be used as neuroleptics (in particular atypical),antidepressants, sedatives, hypnotics, CNS protectants or musclerelaxants. Several of the active qualities can occur in combination inone compound according to the invention. Demonstration of thepharmacological action is carried out both in vivo and in vitro,substance characterization in particular being possible as a result ofthe in some cases very high and selective affinity to receptor subtypes,e.g. dopamine D₁, D₂, D₃ and especially D₄ receptors; serotonin 1A, 1Dand 2 receptors, alpha 1 and 2 receptors; histamine 1 and muscarinereceptors.

The following methods were used for the in vivo characterization:

a) Effect on orientation motility

In a new environment, mice show increased exploratory behavior which ismanifested by increased motor activity. This motor activity is measuredin light barrier cages for 0-30 min after the animals (female NMRI mice)have been placed in the cages.

ED50: dose which reduces the motor activity by 50% in comparison withplacebo-treated controls.

b) Apomorphine antagonism

Female NMRI mice receive 1.21 mg/kg of apomorphine s.c. At this dose,apomorphine leads to motor activation which is manifested by continuousclimbing when the animals are kept in wire mesh cages. The climbing isassessed using a score (every 2 min for 30 min):

0: animal has four paws on the floor

1: animal has two paws on the wire

2: animal has four paws on the wire (is climbing).

The climbing behavior can be inhibited by pretreatment withantipsychotics.

ED50: dose which inhibits the climbing activity of the animals by 50% incomparison with placebo-treated controls.

c) Methamphetamine antagonism

Female NMRI mice receive 1 mg/kg of methamphetamine p.o. and, after 30min, are placed in light barrier cages to measure the motor activity (2animals/cage, 4 cages/dose). The test substances are given orally 30 minbefore methamphetamine. The increase in activity due to methamphetamineis calculated for the period 15 to 60 min after the animals have beenplaced in the measurement cages as the difference betweenmethamphetamine controls and placebo controls and set equal to 100%. TheED100 is the dose of the test substance which completely abolishes theincrease in activity.

d) L-5-HTP antagonism

Female Sprague-Dawley rats receive L-5-HTP in a dose of 316 mg/kg i.p.The animals subsequently develop an excitation syndrome of which thesymptoms

forepaw treading and

tremor

are assessed with the aid of a score (0=not present, 1=moderate,2=clearly marked) every 10 min in the period from 20 to 60 min afterL-5-HTP administration. On average, a score of 17 is achieved afterL-5-HTP administration. The test substances are given p.o. 60 min beforeL-5-HTP. The ED50 is calculated as the dose which on average decreasesthe control score by 50%.

The methods mentioned are suitable for characterizing substances asantipsychotics; in particular, the inhibition of motor stimulationinduced by methamphetamine is regarded as predictive of an antipsychoticeffect. A serotonin-antagonistic effect may be shown by the inhibitionof the L-5-HTP syndrome, a type of effect which is characteristic of theatypical neuroleptics.

The novel compounds show a good effect in these tests.

The invention accordingly also relates to a therapeutic composition,which contains a compound of the formula I or its pharmacologicallytolerable acid addition salt as active compound in addition to customaryexcipients and diluents, and the use of the novel compounds in thecontrol of diseases.

The compounds according to the invention can be administered in acustomary manner orally or parenterally, intravenously orintramuscularly.

The dosage depends on the age, condition and weight of the patient andon the mode of administration. As a rule, the daily dose of activecompound is from about 1 to 100 mg/kg of body weight on oraladministration and from 0.1 to 10 mg/kg of body weight on parenteraladministration.

The novel compounds can be used in conventional solid or liquidpharmaceutical administration forms, e.g. as tablets, film tablets,capsules, powders, granules, coated tablets, suppositories, solutions,ointments, creams or sprays. These are prepared in a customary manner.The active compounds can in this case be processed with the customarypharmaceutical auxiliaries such as tablet binders, fillers,preservatives, tablet disintegrants, flow regulators, plasticizers,wetting agents, dispersants, emulsifiers, solvents, release-delayingagents, antioxidants and/or propellant gases (cf. H. Sucker et al.:Pharmazeutische Technologie Pharmaceutical Technology!, Thieme-Verlag,Stuttgart, 1978). The administration forms thus obtained normallycontain the active compound in an amount from 1 to 99% by weight.

The substances of the formulae II and III required as startingsubstances for the synthesis of the novel compounds are known or can besynthesized from similar starting materials according to the preparationmethods described in the literature.

The following examples serve to illustrate the invention:

Preparation of the precursors

A. exo-2-Phenyl-3-methyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane

a) 6-Phenyl-7-methyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane-2,4-dione

17.8 g (200 mmol) of sarcosine, 15.2 ml (150 mmol) of benzaldehyde and9.7 g (100 mmol) of maleimide were suspended in 500 ml of toluene andrefluxed in a Dean and Stark apparatus for 3 h. A further 17.8 g (200mmol) of sarcosine and 15.2 ml (150 mmol) of benzaldehyde were thenadded and the mixture was refluxed for a further hour. After cooling, 50g of sodium sulfate were added, stirred for a few minutes and filteredoff. The filtrate was concentrated and the residual viscous oil (37.2 g)was purified by column chromatography (silica gel, eluentdichloromethane/methanol 98:5). In this manner, 4.2 g (18%) of enrichedendo adduct (endo:exo=80:20) and 10.7 g (47%) of enriched exo adduct(exo:endo=80:20) were obtained.

b) exo-2-Phenyl-3-methyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane

A solution of 8.5 g (37 mmol) of enrichedexo-6-phenyl-7-methyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane-2,4-dione in130 ml of absolute tetrahydrofuran was added dropwise at roomtemperature with good stirring in the course of 25 min to a suspensionof 7.0 g (185 mmol) of lithium aluminum hydride in 180 ml of absolutetetrahydrofuran. After the slightly exothermic reaction had subsided,the mixture was stirred at room temperature for a further 18 h. Whilecooling in ice, 70 ml of ten percent sodium hydroxide solution were thenadded dropwise with vigorous stirring and the mixture was allowed tocome to room temperature with stirring. The precipitated hydroxides werefiltered off with suction and washed several times with tetrahydrofuran,and the combined filtrates were concentrated. 6.3 g (84%) of a pale oilwere isolated.

B. endo-2-Phenyl-3-methyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane

In a similar manner to procedure A.b), 3.0 g (81%) of cloudy oil wereobtained from 4.2 g (18 mmol) of enrichedendo-6-phenyl-7-methyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane-2,4-dioneand 3.5 g (91 mmol) of lithium aluminum hydride.

C. 3-Phenyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane

a) 7-Benzyl-3-phenyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane-2,4-dione

20.1 g (100 mmol) of N-benzylglycine hydrochloride, 7.5 g (250 mmol) ofparaformaldehyde and 8.7 g (50 mmol) of N-phenylmaleimide were suspendedin 500 ml of toluene and 17.4 ml (100 mmol) of N-ethyldiisopropylaminewere finally added. The reaction mixture was refluxed for 30 min in aDean and Stark apparatus and then filtered through sodium sulfate, andthe filtrate was concentrated. The residual viscous oil (18.6 g) waspurified by column chromatography (silica gel, eluent dichloromethane).8.7 g (56%) of a pale oil were obtained.

b) 7-Benzyl-3-phenyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane

A solution of 8.7 g (28 mmol) of7-benzyl-3-phenyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane-2,4-dione in 100ml of absolute tetrahydrofuran was slowly added dropwise at roomtemperature to a suspension of 2.65 g (71 mmol) of lithium aluminumhydride in 75 ml of absolute tetrahydrofuran. The mixture was thenstirred under reflux for a further 2 h. Then, while cooling in ice, 30ml of ten percent sodium hydroxide solution were slowly added dropwise,and the precipitated hydroxides were filtered off with suction. Washingwith tetrahydrofuran and concentration of the combined filtratesafforded 7.2 g of a cloudy oil, which was purified by columnchromatography (silica gel, dichloromethane/methanol 97:3). Yield: 5.8 g(73%) of clear oil.

c) 3-Phenyl-1,5-cis-3,7-diazabicyclo 3.3.0!octane

5.8 g (21 mmol) of 7-benzyl-3-phenyl-1,5-cis-3,7-diazabicyclo3.3.0!octane were dissolved in 170 ml of methanol, and 0.7 g ofpalladium on carbon (10%) was added. A solution of 6.6 g (104 mmol) ofammonium formate in 7 ml of water was then added dropwise with stirring.The mixture was then stirred for 3 h at 50° C., a further 0.5 g ofpalladium on carbon (10%) was subsequently added, and the mixture wasstirred for a further hour at 50° C. The catalyst was filtered off withsuction and washed well with methanol, and the combined filtrates wereconcentrated to dryness. The residue was taken up in water, adjusted topH 9-10 and extracted three times with dichloromethane. Drying andconcentration of the organic phase afforded 3.0 g of white solid, whichwas digested in a little ether. Filtering off with suction and dryingyielded 1.7 g (43%) of colorless, fine crystals.

D. exo-6-Phenyl-3-azabicyclo 3.1.0!hexane

a) cis-1,2-bis(Hydroxymethyl)trans-3-phenylcyclopropane

A solution of 20.0 g (85 mmol) of dimethyltrans-3-phenyl-cis-1,2-cyclopropanedicarboxylate in 250 ml of absolutetetrahydrofuran was slowly added dropwise to a suspension of 7.9 g (213mmol) of lithium aluminum hydride in 150 ml of absolute tetrahydrofuranwhile cooling in ice at 0° C. The mixture was slowly allowed to come toroom temperature and was stirred for 18 h. Then, 70 ml of ten percentsodium hydroxide solution were slowly added dropwise while cooling inice, and the precipitated hydroxides were filtered off with suction andwashed with tetrahydrofuran. Concentration of the filtrate yielded 14.7g (97%) of viscous, yellow oil.

b) cis-1,2-bis(Methanesulfonyloxymethyl)trans-3-phenylcyclopropane

A solution of 14.7 g (82 mmol) ofcis-1,2-bis(hydroxymethyl)trans-3-phenylcyclopropane in 70 ml ofabsolute pyridine was added dropwise at -5° C. to a solution of 32.2 g(281 mmol) of methanesulfonyl chloride in 350 ml of absolute pyridinesuch that the internal temperature did not rise above 0° C. and themixture was stirred for a further 3 h at -5° C. The cold reactionmixture was then poured onto ice-water to which 60 ml of conc. sulfuricacid had previously been added. The mixture was stirred for a further 1h, and the supernatant solution was decanted from the oily precipitatedeposited, the latter was taken up in a little dimethylformamide andthis solution was poured onto ice-water with stirring. After stirringfor 1 h, the fine crystalline precipitate was filtered off with suction,washed with water and dried. 19.6 g (78%) of pale powder were obtained.

c) 3-(4-Methoxyphenylmethyl)exo-6-phenyl-3-azabicyclo 3.1.0!hexane

5.0 g (16.6 mmol) ofcis-1,2-bis(methanesulfonyloxymethyl)-trans-3-phenylcyclopropane wereintroduced into 6.8 g (50 mmol) of 4-methoxybenzylamine and the mixturewas heated at 100° C. for 2 h with good stirring. After cooling, themixture was dissolved in methylene chloride, and the organic phase waswashed twice with water and concentrated after drying with sodiumsulfate. The crude product (4.9 g) was purified by column chromatography(silica gel, eluent methylene chloride/methanol 99:1). 2.2 g (48%) ofproduct were isolated as a yellow oil.

d) exo-6-Phenyl-3-azabicyclo 3.1.0!hexane

2.2 g (7.9 mmol) of 3-(4-methoxyphenylmethyl)exo-6-phenyl-3-azabicyclo3.1.0!hexane were dissolved in 70 ml of methanol and 0.6 g of palladiumon carbon (10%) was added. A solution of 2.5 g (39 mmol) of ammoniumformate in 3 ml of water was then added dropwise with stirring. Themixture was then stirred for 1 h at 50° C. The catalyst was filtered offwith suction and washed well with methanol, and the combined filtrateswere concentrated to dryness. The residue was taken up in water,adjusted to pH 9-10 and extracted three times with dichloromethane.Drying and careful concentration of the organic phase at a maximum bathtemperature of 30° C. afforded 1.1 g (88%) of product as a yellow oil.

E. 6-(4-Fluorophenyl)-1,5-cis-3-azabicyclo 3.3.0!oct-6-ene

a) 3-Benzyl-6-(4-fluorophenyl)-6-hydroxy-1,5-cis-3-azabicyclo3.3.0!octane

First 1.4 g (56 mmol) of magnesium turnings and then a solution of 9.4 g(54 mmol) of 4-bromo-1-fluorobenzene in 55 ml of absolutetetrahydrofuran were added dropwise under nitrogen to 20 ml of absolutetetrahydrofuran. After the weakly exothermic reaction had subsided, themixture was stirred for a further 1 h. A solution of 10.5 g (49 mmol) of3-benzyl-6-oxo-1,5-cis-3-azabicyclo 3.3.0!octane (K. Miyajima, M.Takemoto and K. Achiwa, Chem. Pharm. Bull. 39 (1991), 3175) in 40 ml ofabsolute tetrahydrofuran was then added dropwise and the mixture wassubsequently refluxed for 5 h. 50 ml of a saturated ammonium chloridesolution were then added dropwise while cooling in ice, and theprecipitated hydroxides were filtered off with suction and washed withtetrahydrofuran. The combined filtrates were concentrated, and theresidue was taken up in water, adjusted to pH 11 with ten percent sodiumhydroxide solution and extracted twice with dichloromethane. The organicphase was washed once with saturated sodium chloride solution, driedover sodium sulfate and concentrated. The residual oil (14.8 g) waspurified by column chromatography (silica gel, eluentdichloromethane/methanol 98.5:1.5). 11.5 g (75%) of yellow oil wereobtained.

b) 6-(4-Fluorophenyl)-6-hydroxy-1,5-cis-3-azabicyclo 3.2.0!octane

9.0 g (29 mmol) of3-benzyl-6-(4-fluorophenyl)-6-hydroxy-1,5-cis-3-azabicyclo 3.3.0!octanewere dissolved in 250 ml of methanol and 2.0 g of palladium on carbon(10%) were added. A solution of 9.1 g (145 mmol) of ammonium formate in11 ml of water was then added dropwise with stirring and the mixture wasrefluxed for a further 3 h after addition was complete. The catalyst wasfiltered off with suction and washed well with methanol, and thecombined filtrates were concentrated to dryness. The residue was takenup in water, adjusted to pH 9-10 with ten percent sodiumhydroxidesolution and extracted twice with dichloromethane. Drying andconcentration of the organic phase yielded 5.4 g (84%) of yellowish oil.

c) 6-(4-Fluorophenyl)-1,5-cis-3-azabicyclo 3.3.0!oct-6-ene

6.9 g (31 mmol) of 6-(4-fluorophenyl)-6-hydroxy-1,5-cis-3-azabicyclo3.3.0!octane were taken up in 50 ml of half-concentrated hydrochloricacid and the mixture was refluxed for 5 h. It was then diluted withwater while cooling in ice, adjusted to pH 11 with concentrated sodiumhydroxide solution and extracted twice with dichloromethane. Drying andconcentration of the organic phase yielded a dark oil (5.9 g), which waspurified by column chromatography (silica gel, eluent methanol/aqueousammonia solution 95:5). 5.3 g (84%) of brown oil were obtained.

F. 6-(4-Fluorophenyl)-1,5-cis-3-azabicyclo 3.3.0!octane

5.3 g (26.1 mmol) of 6-(4-fluorophenyl)-1,5-cis-3-azabicyclo3.3.0!oct-6-ene were dissolved in 100 ml of methanol and 1.0 g ofpalladium on carbon (10%) was added. The reaction mixture wascatalytically hydrogenated under normal conditions. The catalyst wasfiltered off with suction and washed well with methanol, and thecombined filtrates were concentrated to dryness. 4.4 g (82%) of productwas isolated as an exo/endo diastereomer mixture, which was separated bycolumn chromatography (silica gel, eluent methanol/ammonium hydroxide90:10).

G. exo-7-Phenyl-1,5-cis-3-azabicyclo 3.3.0!octane

A reaction mixture of 9.9 g (50 mmol) of 3-benzyl-1,5-cis-3-azabicyclo3.3.0!oct-6-ene (K. Miyajima, M. Takemoro and K. Achiwa, Chem. Pharm.Bull. 39 (1991) 3175), 14.0 ml (125 mmol) of iodobenzene, 0.9 g (4.0mmol) of palladium(II) acetate, 2.1 g (8.0 mmol) of triphenylphosphine,4.3 g (50 mmol) of piperidine and 2.3 g (50 mmol) of formic acid in 100ml of dimethylformamide was heated at 80° C. for 6 h with good stirring.After concentrating the mixture in an oil pump vacuum, the residue waspartitioned between water and methylene chloride, the mixture wasacidified with ten percent hydrochloric acid, and the organic phase wasconcentrated after drying with sodium sulfate. The crude product waspurified by column chromatography (silica gel, eluent ethylacetate/n-hexane 1:1). 3.6 g (26%) of the N-benzyl derivative wereisolated and converted by catalytic hydrogenation in a similar manner toExample F to the final product (yellow oil).

The following can be prepared in a similar manner (see Example O):

exo-7-(p-fluorophenyl)-1,5-cis-3-azabicyclo 3.3.0!octane

H. endo-6-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!nonane

a) endo-3-p-Fluorophenylcyclohex-4-ene-cis-1,2-dicarboxylic anhydride

53.0 g (358 mmol) of trans-1-p-fluorophenyl-1,3-butadiene in 100 ml oftoluene were slowly heated to 100° C. with 34.3 g (350 mmol) of maleicanhydride while stirring well and the mixture was kept at thistemperature for 1.5 h. After cooling, the mixture was concentrated toone half and the product was allowed to crystallize while cooling in anice bath. The crystals were filtered off with suction and washed with alittle cold toluene. 59 g (69%) of product of m.p. 88°-90° C. wereisolated.

b) cis-3-p-Fluorophenyl-cis-1,2-bis(hydroxymethyl)-4-cyclohexene

A solution of 12.0 g (49 mmol) ofendo-3-p-fluorophenylcyclohex-4-ene-cis-1,2-dicarboxylic anhydride in 60ml of tetrahydrofuran was added dropwise at room temperature and withgood stirring to 3.5 g (92 mmol) of lithium aluminum hydride in 170 mlof absolute tetrahydrofuran in the course of 45 min. After stirring for1.5 h, the mixture was refluxed for a further 2 h. After cooling, tenpercent sodium hydroxide solution was carefully added dropwise whilecooling in ice and with good stirring, and the precipitated hydroxideswere filtered off with suction. The filtrate was concentrated todryness, and the residue was partitioned between ten percent sodiumhydroxide solution and methyl t-butyl ether. The aqueous phase wasre-extracted twice with methyl t-butyl ether, and the organic phase wasthen concentrated after drying with sodium sulfate. 8.9 g (77%) ofproduct were isolated as a clear oil.

c)cis-3-p-Fluorophenyl-cis-1,2-bis(methanesulfonyloxymethyl)-cyclohex-4-ene

19.7 g (84 mmol) ofcis-3-p-fluorophenyl-cis-1,2-bis(hydroxymethyl)cyclohex-4-ene in 70 mlof pyridine were added dropwise at 0° C. with good stirring to asolution of 28.6 g (250 mmol) of methanesulfonyl chloride in 100 ml ofpyridine and the mixture was stirred for 2 h at 0° C. It wassubsequently poured onto ice-water into which 64 ml of concentratedsulfuric acid had been introduced, and the mixture was extracted twicewith methylene chloride. The organic phases were washed twice with tenpercent sulfuric acid and concentrated after drying with sodium sulfate.30.3 g (92%) of product were isolated as a pale oil.

d) 3-Benzylendo-6-p-fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!-non-7-ene

21.8 g (56 mmol) ofcis-3-p-fluorophenyl-cis-1,2-bis(methanesulfonyloxymethyl)cyclohex-4-enewere introduced in portions into 20 ml (183 mmol) of benzylamine withgood stirring (exothermic reaction). The mixture was subsequently heatedat 130° C. for a further 2 h. After cooling, 200 ml of methyl t-butylether were added to the reaction mixture, which was stirred until itcrystallized. After filtering off the crystals with suction and washingwith methyl t-butyl ether, the filtrate was washed twice with aqueousammonia solution and the organic phase was concentrated after dryingwith sodium sulfate. The crude product (16.5 g) was purified by columnchromatography (silica gel, eluent ethyl acetate/n-hexane 6:4). 10.5 g(61%) of product were isolated as a pale oil.

e) endo-6-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!nonane

10.0 g (32 mmol) of 3-benzyl-endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-ene in 200 ml of methanol were catalytically hydrogenated atroom temperature in the presence of 1.3 g of palladium on carbon (10%).After filtering off the catalyst with suction and washing with methanol,7.8 g of crude product were isolated after concentration as a pale oilwhich was purified by column chromatography (silica gel, eluentmethanol/aqueous ammonia solution 85:15). 4.6 g (66%) of product of m.p.76°-78° C. were isolated.

The following can be prepared in a similar way:

f) endo-6-phenyl-1,5-cis-3-azabicyclo 4.3.0!nonane g)endo-6-p-trifluoromethylphenyl-1,5-cis-3-azabicyclo 4.3.0!nonane

I. endo-6-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!non-7-ene

20 ml of ammonia were injected into a 0.3 l stirred autoclave containing7.6 g (19.4 mmol) ofcis-3-p-fluorophenyl-cis-1,2-bis-(methanesulfonyloxymethyl)cyclohex-4-enein 100 ml of toluene and the mixture was heated at 150° C. for 5 h underautogenous pressure. The reaction mixture was then poured onto ice-waterand the organic phase was washed with water after filtering off theinsoluble components with suction. After drying and concentration, 4.4 gof crude product were isolated and purified by column chromatography(silica gel, eluent methanol/aqueous ammonia solution 85:15). 0.9 g(21%) of product were isolated as a colorless oil.

K. 6-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!non-6-ene

a) endo-3-p-Fluorophenylcyclohex-4-ene-cis-1,2-dicarboximide

50.0 g (338 mmol) of trans-1-p-fluorophenyl-1,3-butadiene in 100 ml oftoluene were slowly heated to 100° C. with 32.0 g (330 mmol) ofmaleimide while stirring well and the mixture was kept at thistemperature for 2 h. After cooling, it was concentrated to one half andthe product was allowed to crystallize while cooling in an ice-bath. Thecrystals were filtered off with suction and washed with a little coldtoluene. 69.7 g (86%) of product of m.p. 184°-186° C. were isolated.

b) 3-p-Fluorophenylcyclohex-3-ene-cis-1,2-dicarboximide

9.8 g (40 mmol) ofendo-3-p-fluorophenylcyclohex-4-ene-cis-1,2-dicarboximide in 100 ml ofdimethylformamide were treated in portions with 2.4 g (80 mmol) ofsodium hydride (80%) with good stirring (exothermic reaction). Themixture was stirred for a further 2 h at 45° C. and subsequently pouredonto ice-water after cooling. 100 ml of methyl t-butyl ether were addedafter acidifying with ten percent hydrochloric acid and the mixture wasstirred vigorously. The pale solid was filtered off with suction, washedwith a little methyl t-butyl ether and water and dried under reducedpressure at 50° C. The crude product was purified by columnchromatography (silica gel, eluent methylene chloride/methanol 97:3).6.7 g (68%) of product (main polar zone) of m.p. 197°-199° C. wereisolated.

c) 6-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!non-6-ene

A solution of 4.0 g (16.4 mmol) of3-p-fluorophenylcyclohex-3-ene-cis-1,2-dicarboximide in 50 ml oftetrahydrofuran was added dropwise at room temperature and with goodstirring to 1.96 g (51 mmol) of lithium aluminum hydride in 60 ml ofabsolute tetrahydrofuran in the course of 45 min. After stirring for 1.5h the mixture was refluxed for a further 3 h. After cooling, ten percentsodium hydroxide solution was carefully added dropwise with ice-coolingstirring and the precipitated hydroxides were filtered off with suction.The filtrate was concentrated to dryness, and the residue waspartitioned between water and methyl t-butyl ether at pH=10. The organicphase was extracted with five percent hydrochloric acid, renderedalkaline with concentrated sodium hydroxide solution and extracted twicewith methyl t-butyl ether. After drying and concentration, 1.6 g (45%)of product were obtained as a pale oil.

The following can be prepared in a similar manner:

d) 6-phenyl-1,5-cis-3-azabicyclo 4.3.0!non-6-ene

L. exo-6-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!nonane

a) exo-3-p-Fluorophenylcyclohex-4-ene-cis-1,2-dicarboximide

15.0 g (61 mmol) ofendo-3-p-fluorophenylcyclohex-4-ene-cis-1,2-dicarboximide in 100 ml ofdimethylformamide were treated in portions with good stirring with 12.9g (94 mmol) of finely pulverized potassium carbonate and the mixture waskept for 2 h at 100° C. and then poured onto ice-water after cooling.After acidifying with concentrated hydrochloric acid, it was extractedwith methyl t-butyl ether and the organic phase was washed with tenpercent hydrochloric acid. After drying and concentration, 18.1 g ofcrude product were isolated, which was washed with 50 ml of ether bystirring. 12.1 g (81%) of colorless crystals of m.p. 119°-121° C. wereisolated. The configuration of the product was confirmed by the crystalstructure analysis.

b) exo-6-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!non-7-ene

A solution of 6.5 g (26 mmol) of3-p-fluorophenylcyclohex-4-ene-cis-1,2-dicarboximide in 60 ml oftetrahydrofuran was added dropwise at room temperature and with goodstirring to 3.2 g (84 mmol) of lithium aluminum hydride in 120 ml ofabsolute tetrahydrofuran within the course of 45 min. After stirring for1.5 h, the mixture was refluxed for a further 3 h. After cooling, tenpercent sodium hydroxide solution was carefully added dropwise with goodstirring and with ice cooling and the precipitated hydroxides werefiltered off with suction. The filtrate was concentrated to dryness, andthe residue was partitioned between ten percent hydrochloric acid andmethyl t-butyl ether. The aqueous phase was washed with methyl t-butylether, rendered alkaline with concentrated sodium hydroxide solution andextracted twice with methyl t-butyl ether. After drying andconcentration, 3.6 g (64%) of product were isolated as a pale oil.

c) exo-6-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!nonane

Obtained by catalytic hydrogenation ofexo-6-p-fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!non-7-ene according tothe procedure of Example F: yield 89%.

The following can be prepared in a similar manner:

d) exo-6-phenyl-1,5-cis-3-azabicyclo 4.3.0!nonane

M. exo-7-Phenyl-1,5-cis-3-azabicyclo 4.3.0!non-8-ene

a) exo-4-Phenylcyclohex-5-ene-cis-1,2-dicarboximide

A mixture of 15.1 g (100 mmol) of cyclohex-4-ene-cis-1,2-dicarboximide,28.0 ml (250 mmol) of iodobenzene, 1.8 g (8.0 mmol) of palladium(II)acetate, 2.1 g (8.0 mmol) of triphenylphosphine, 8.5 g (100 mmol) ofpiperidine and 4.6 g (100 mmol) of formic acid in 200 ml ofdimethylformamide was heated at 80° C. for 6 h with good stirring. Afterconcentration of the mixture in an oil pump vacuum, the residue waspartitioned between water and methylene chloride, the mixture wasacidified with ten percent hydrochloric acid and the organic phase wasconcentrated after drying with sodium sulfate. The crude product (31 g)was purified by column chromatography (silica gel, eluent ethylacetate/n-hexane 1:1). 2 main fractions were isolated: the polar zoneyielded 3.9 g (17%) of product as a yellowish oil.

b) exo-7-Phenyl-1,5-cis-3-azabicyclo 4.3.0!non-8-ene

1.0 g (26 mmol) of lithium aluminum hydride was added in portions to 3.0g (17.2 mmol) of exo-4-phenylcyclohex-5-ene-cis-1,2-dicarboximide in 150ml of tetrahydrofuran at room temperature and with good stirring. Afterstirring for 0.5 h, the mixture was refluxed for a further 3 h. Aftercooling, ten percent sodium hydroxide solution was carefully addeddropwise with good stirring and with ice cooling and the precipitatedhydroxides were filtered off with suction and washed withtetrahydrofuran. The filtrate was concentrated to dryness, and theresidue was partitioned between water and methyl t-butyl ether at pH=10.After drying and concentration, 3.2 g of crude product were isolated asa dark oil. The crude product was purified by column chromatography(silica gel, eluent methylene chloride/methanol 1:1). 1.1 g (32%) ofproduct were isolated as a pale oil.

N. 7-Phenyl-3-azabicyclo 4.3.0!non-1-ene

a) 4-Phenylcyclohex-1-ene-1,2-dicarboximide

The non-polar main fraction from column chromatography of Example M.a)yielded 3.2 g (15%) of product as a colorless oil/crystal mixture.

b) 7-Phenyl-3-azabicyclo 4.3.0!non-1-ene

In a similar manner to Example M.b), reduction with lithium aluminumhydride yielded 0.7 g (25%) of product as a pale oil.

O. exo-7-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!nonane

a) 4-p-Fluorophenylcyclohex-1-ene-1,2-dicarboximide

A reaction mixture of 45.3 g (300 mmol) ofcyclohex-4-ene-cis-1,2-dicarboximide, 82.5 ml (750 mmol) ofp-bromofluorobenzene, 5.4 g (24 mmol) of palladium(II) acetate, 6.3 g(24 mmol) of triphenylphosphine, 29.7 ml (300 mmol) of piperidine and11.4 ml (300 mmol) of formic acid in 600 ml of dimethylformamide washeated at 95° to 100° C. for 6 h with good stirring. After concentratingthe mixture in an oil pump vacuum, the residue was partitioned betweenwater and methylene chloride, the mixture was acidified with ten percenthydrochloric acid, the organic phase was washed with ten percenthydrochloric acid and the organic phase was concentrated after dryingwith sodium sulfate. The crude product (71 g) was stirred in 350 ml ofethyl acetate and the brown solid was filtered off with suction andwashed with ethyl acetate. Concentration of the filtrate afforded 56 gof crude product, which was purified by column chromatography (silicagel, eluent ethyl acetate/n-hexane 40:60). 2 main fractions wereisolated: the non-polar zone yielded 13.3 g of product which was washedwith a 1:1 mixture of ethyl acetate and n-hexane by stirring. 8.9 g(12%) of product of m.p. 136°-137° C. were isolated.

b) 7-p-Fluorophenyl-3-azabicyclo 4.3.0!non-1-ene

4.5 g (118 mmol) of lithium aluminum hydride were added in portions to9.4 g (38 mmol) of 4-p-fluorophenylcyclohex-1-ene-1,2-dicarboximide in300 ml of tetrahydrofuran during the course of 45 min at roomtemperature and with good stirring. After stirring for 0.5 h, themixture was refluxed for a further 6 h. After cooling, ten percentsodium hydroxide solution was carefully added dropwise with goodstirring and with ice cooling and the precipitated hydroxides werefiltered off with suction and washed with tetrahydrofuran. The filtratewas concentrated to dryness and the residue was partitioned betweenwater and methyl t-butyl ether at pH=10. The organic phase wassubsequently extracted twice with ten percent hydrochloric acid and theacidic aqueous phase was rendered alkaline again after this withconcentrated sodium hydroxide solution. It was then extracted twice withmethyl t-butyl ether. After drying and concentration, 1.8 g (22%) ofproduct were isolated as a pale oil.

c) exo-4-p-Fluorophenylcyclohex-5-ene-cis-1,2-dicarboximide

The polar main fraction from column chromatography of Example O.a)yielded 9.2 g of product, which was digested in a little ether. 4.3 g(6%) of product of m.p. 139° to 142° C. were isolated.

d) exo-7-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!non-8-ene

In a similar manner to Example O.b), reduction with lithium aluminumhydride yielded 2.4 g (63%) of product as a pale oil.

e) exo-7-p-Fluorophenyl-1,5-cis-3-azabicyclo 4.3.0!nonane

Catalytic hydrogenation in a similar manner to Example F yielded 2.2 g(92%) of product as a yellowish oil.

P. 6-Phenyl-1,5-cis-8-oxa-3,7-diazabicyclo 3.3.0!oct-6-ene

5.0 g (41 mmol) of benzaldehyde oxime in 50 ml of methylene chloridewere treated with 6.8 g (41 mmol) of 1-trifluoroacetyl-3-pyrroline. 36.9g (74 mmol) of a five percent sodium hypochlorite solution were thenadded dropwise while stirring well (exothermic reaction). After stirringfor 2 h, the mixture was poured onto ice-water, rendered alkaline withconcentrated ammonia solution and extracted twice with methylenechloride. The combined organic phases were washed with water andconcentrated after drying with sodium sulfate. The crude product (13.1g) was purified by column chromatography (silica gel, eluent methylenechloride). 3.5 g (30%) of the trifluoroacetyl derivative were isolatedand were hydrolyzed during a further 30 min at room temperature in 2Nmethanolic sodium hydroxide solution to give the final product of m.p.78°-80° C.

Reduction with sodium cyanoborohydride affordedexo/endo-6-phenyl-1,5-cis-8-oxa-3,7-diazabicyclo 3.3.0!octane as a paleoil.

The following can be prepared in a similar manner:

6-p-fluorophenyl-1,5-cis-8-oxa-3,7-diazabicyclo 3.3.0!oct-6-eneexo/endo-6-p-fluorophenyl-1,5-cis-8-oxa-3,7-diazabicyclo 3.3.0!octaneEXAMPLE 1 N-(2- exo-6-Phenyl-7-methyl-1,5-cis-3,7-diazabicyclo3.3.0!octan-3-yl!ethyl)-4-fluorobenzamide

2.5 g (12.4 mmol) of exo-6-phenyl-7-methyl-1,5-cis-3,7-diazabicyclo-3.3.0!octan in 50 ml xylene were treated with 2.5 g (12.4 mmol) ofN-(2-chloroethyl)-4-fluorobenzamide and with 1.7 g (12.4 mmol) of finelypulverized potassium carbonate and 0.5 g of potassium iodide andrefluxed with good stirring for 2 h.

After cooling, the mixture was concentrated on a rotary evaporator andthe residue was partitioned between methylene chloride and water.

The aqueous phase was re-extracted twice with methylene chloride and theorganic phase was then concentrated after drying with sodium sulfate.The crude product (4.9 g) was purified by column chromatography (silicagel, eluent methylene chloride/methanol 95:5). 2.5 g (55%) of product ofm.p. 108°-110° C. (hydrochloride) were obtained.

The following can be prepared in a similar manner:

2. N-(2- endo-6-phenyl-7-methyl-1,5-cis-3,7-diazabicyclo3.3.0!octan-3-yl!ethyl)-4-fluorobenzamide,

3. N-(2- exo-6-p-fluorophenyl-7-methyl-1,5-cis-3,7-diazabicyclo3.3.0!octan-3-yl!ethyl)-4-fluorobenzamide,

4. N-(2- exo-6-p-trifluoromethylphenyl-7-methyl-1,5-cis-3,7-diazabicyclo3.3.0!octan-3-yl!ethyl)benzamide,

5. N-(2- exo-6-m-chlorophenyl-7-methyl-1,5-cis-3,7-diazabicyclo3.3.0!octan-3-yl!ethyl)benzamide,

6. N-(2- exo-6-p-methoxyphenyl-7-methyl-1,5-cis-3,7-diazabicyclo3.3.0!octan-3-yl!ethyl)-4-chlorobenzamide,

7. N-(2- exo-6-phenyl-7-methyl-1,5-cis-3,7-diazabicyclo3.3.0!octan-3-yl!ethyl)naphthalene-1-carboxamide,

8. 1-(4-fluorophenyl)-4-exo-6-p-fluorophenyl-7-methyl-1,5-cis-3,7-diazabicyclo3.3.0!octan-3-yl!butan-1-one,

9. 1-(4-fluorophenyl)-4-exo-6-p-fluorophenyl-7-methyl-1,5-cis-3,7-diazabicyclo3.3.0!octan-3-yl!butan-1-ol.

EXAMPLE 10 N-(2- exo-6-p-Fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)benzamide

1.6 g (7.3 mmol) of exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!nonane in 50 ml of xylene were treated with 2.7 g (14.6 mmol) ofN-(2-chloroethyl)benzamide and with 1.4 g (10.0 mmol) of finelypulverized potassium carbonate and 0.5 g of potassium iodide andrefluxed with good stirring for 8 h.

After cooling, the mixture was concentrated on a rotary evaporator andthe residue was partitioned between methylene chloride and water(pH=10).

The aqueous phase was re-extracted twice with methylene chloride and theorganic phase was then concentrated after drying with sodium sulfate.The crude product (4.0 g) was purified by column chromatography (silicagel, eluent methylene chloride/methanol 93:7). 1.3 g (49%) of product ofm.p. 160°-162° C. (maleate) were obtained.

EXAMPLE 11 1-(2- exo-6-p-Fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)naphthalene

1.6 g (7.3 mmol) of exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!nonane in 50 ml of xylene were treated with 1.7 g (7.3 mmol) of1-(2-bromo)ethylnaphthalene and with 1.4 g (10.0 mmol) of finelypulverized potassium carbonate and 0.5 g of potassium iodide andrefluxed with good stirring for 9 h.

After cooling, the mixture was concentrated on a rotary evaporator andthe residue was partitioned between methylene chloride and water(pH=10).

The aqueous phase was re-extracted twice with methylene chloride and theorganic phase was then concentrated after drying with sodium sulfate.The crude product (3.5 g) was purified by column chromatography (silicagel, eluent methylene chloride/methanol 96:4). 1.8 g (66%) of product ofm.p. 99°-100° C. (decomposition, fumarate) were obtained.

The following can be prepared in a simmilar manner:

12. 1-(4-fluorophenyl)-4- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!butan-1-one,

13. 1-(4-fluorophenyl)-4- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!butan-1-ol,

14. N-(2- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)-2-(N-methyl)aminobenzamide,

15. N-(2- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)-5-chlorothien-2-ylcarboxamide,

16. N-(2- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)inden-3-carboxamide,

17. N-(2- exo-6-phenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)-4-fluorobenzamide,

18. N-(2- exo-6-phenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)naphthalene-1-carboxamide,

19. 1-(2- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)naphthalene,

20. 1-(4-fluorophenyl)-4- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!butan-1-one,

21. N-(2- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)benzamide,

22. N-(2- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)inden-3-carboxamide,

23. N-(2- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)naphthalene-1-carboxamide,

24. N-(2- exo-6-phenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)-4-fluorobenzamide,

25. N-(2- exo-6-phenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)-3-chloro-1-benzothien-2-ylcarboxamide,

26. 1-(2- 6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!ethyl)naphthalene,

27. 1-(4-fluorophenyl)-4- 6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!butan-1-one,

28. 1-(4-fluorophenyl)-4- 6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!butan-1-ol,

29. N-(2- 6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!ethyl)-2-(N-methyl)aminobenzamide,

30. N-(2- 6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!ethyl)-5-chlorothien-2-yl-carboxamide,

31. N-(2- 6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!ethyl)benzamide,

32. N-(2- 6-phenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!ethyl)-3-chloro-1-benzothien-2-ylcarboxamide,

33. N-(2- 6-p-trifluoromethylphenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!ethyl)naphthalene-1-carboxamide,

34. N-(2- 6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!ethyl)inden-3-carboximide,

35. N-(2- 6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-6-en-3-yl!ethyl)napthalene-1-carboxamide,

36. 1-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)naphthalene,

37. 1-(4-fluorophenyl)-4- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!butan-1-one,

38. 1-(4-fluorophenyl)-4- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!butan-1-ol,

39. N-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!-2-(N-methyl)aminobenzamide,

40. N-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)benzamide,

41. N-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)-5-chlorothien-2-ylcarboxamide,

42. N-(2- endo-6-phenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)-4-fluorobenzamide,

43. N-(2- endo-6-p-trifluoromethylphenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)inden-3-carboxamide,

44. 2-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)naphthalene,

45. N-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)benzamide,

46. N-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)-2-(N-methyl)aminobenzamide,

47. N-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-7-en-3-yl!ethyl)naphthalene-1-carboxamide,

48. 1-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-8-en-3-yl!ethyl)naphthalene,

49. 1-(4-fluorophenyl)-4- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-8-en-3-yl!butan-1-one,

50. N-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-8-en-3-yl!ethyl)benzamide,

51. N-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-8-en-3-yl!ethyl)-5-chlorothien-2-ylcarboxamide,

52. N-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-8-en-3-yl!ethyl)-3-chloro-1-benzothien-2-ylcarboxamide,

53. N-(2- exo-7-phenyl-1,5-cis-3-azabicyclo4.3.0!non-8-en-3-yl!ethyl)inden-3-carboxamide,

54. N-(2- exo-7-phenyl-1,5-cis-3-azabicyclo4.3.0!non-8-en-3-yl!ethyl)naphthalene-1-carboxamide,

55. 1-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)naphthalene,

56. 1-(4-fluorophenyl)-4- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!butan-1-one,

57. 1-(4-fluorophenyl)-4- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!butan-1-ol,

58. N-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)-2-(N-methyl)aminobenzamide,

59. N-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)benzamide,

60. N-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)-5-chlorothien-2-ylcarboxamide,

61. N-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)naphthalene-1-carboxamide,

62. N-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo4.3.0!non-3-yl!ethyl)inden-3-carboxamide,

63. 1-(2- 6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!oct-6-en-3-yl!ethyl)naphthalene,

64. 1-(4-fluorophenyl)-4- 6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!oct-6-en-3-yl!butan-1-one,

65. N-(2- 6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!oct-6-en-3-yl!ethyl)benzamide,

66. N-(2- 6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!oct-6-en-3-yl!ethyl)naphthalene-1-carboxamide,

67. 1-(2- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)naphthalene,

68. 1-(4-fluorophenyl)-4- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!butan-1-ol,

69. N-(2- exo-6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)benzamide,

70. N-(2- exo-6-phenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)naphthalene-1-carboxamide,

71. N-(2- exo-6-phenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)inden-3-carboxamide,

72. 1-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)naphthalene,

73. 1-(4-fluorophenyl)-4- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!butan-1-one,

74. N-(2- endo-6-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)benzamide,

75. N-(2- endo-6-phenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)naphthalene-1-carboxamide,

76. 1-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)naphthalene,

77. 1-(4-fluorophenyl)-4- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!butan-1-one,

78. N-(2- exo-7-p-fluorophenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)benzamide,

79. N-(2- exo-7-phenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)naphthalene-1-carboxamide,

80. N-(2- exo-7-phenyl-1,5-cis-3-azabicyclo3.3.0!octan-3-yl!ethyl)inden-3-carboxamide,

81. N-(2- exo-6-p-fluorophenyl-3-azabicyclo3.1.0!hexan-3-yl!ethyl)-4-fluorobenzamide,

82. N-(2- exo-6-phenyl-3-azabicyclo3.1.0!hexan-3-yl!ethyl)-5-chlorothien-2-ylcarboxamide,

83. N-(2- 6,6-diphenyl-3-azabicyclo3.1.0!hexan-3-yl!-ethyl)naphth-1-ylcarboxamide,

84. N-(2- exo-6-p-fluorophenyl-3-azabicyclo3.1.0!hexan-3-yl!ethyl)-3-chloro-1-benzothien-2-ylcarboxamide,

85. N-(2- exo-6-m-chlorophenyl-3-azabicyclo3.1.0!hexan-3-yl!ethyl)-4-chlorobenzamide,

86. 1-(2- 6-p-fluorophenyl-1-5-cis-8-oxa-3,7-diazabicyclo3.3.0!oct-6-en-3-yl!ethyl)naphthalene,

87. N-(2- 6-p-fluorophenyl-1-5-cis-8-oxa-3,7-diazabicyclo3.3.0!oct-6-en-3-yl!ethyl)benzamide,

88. N-(2- 6-p-fluorophenyl-1-5-cis-8-oxa-3,7-diazabicyclo3.3.0!oct-6-en-3-yl!ethyl)naphthalene-1-carboxamide,

89. N-(2- 6-p-fluorophenyl-1-5-cis-8-oxa-3,7-diazabicyclo3.3.0!oct-6-en-3-yl!ethyl)inden-3-carboxamide,

90. 1-(2- exo/endo-6-p-fluorophenyl-1-5-cis-8-oxa-3,7-diazabicyclo3.3.0!octan-3-yl!ethyl)naphthalene,

91. N-(2- exo/endo-6-p-fluorophenyl-1-5-cis-8-oxa-3,7-diazabicyclo3.3.0!octan-3-yl!ethyl)benzamide,

92. 1-(2- 6-phenyl-1-5-cis-8-oxa-3,7-diazabicyclo3.3.0!oct-6-en-3-yl!ethyl)naphthalene,

93. N-(2- 6-phenyl-1-5-cis-8-oxa-3,7-diazabicyclo3.3.0!oct-6-en-3-yl!ethyl)benzamide.

We claim:
 1. An N-substituted 3-azabicycloalkane derivative of theformula I ##STR5## where B is a 3-, 5- or 6-membered ring which cancontain 1 nitrogen atom and/or 1 oxygen atom and possibly one doublebond,R¹ is a phenyl group which is unsubstituted or mono- ordisubstituted by halogen atoms or C₁ -C₄ -alkyl, trifluoromethyl,hydroxyl, C₁ -C₄ -alkoxy, amino, monomethylamino, dimethylamino, cyanoor nitro groups, R² is a hydrogen atom or a C₁ -C₄ -alkyl radical, n isthe number 2, 3 or 4, A is a hydrogen atom or one of the radicals

    --CO--R.sup.5 or --NR.sup.6 --CO--R.sup.7,

R⁵ is a phenyl group which is unsubstituted or mono- or disubstituted byfluorine, chlorine, bromine or a hydroxyl, nitro, amino, C₁₋₄-alkanoylamino, C₁₋₄ -alkylamino, C₁ -C₄ -alkyl or methoxy group or anaphthyl group which is unsubstituted or substituted by fluorine orchlorine, R⁶ is a hydrogen atom or a methyl group, and R⁷ is a phenylgroup which is mono- or disubstituted by fluorine, chlorine, bromine, C₁-C₄ -alkyl, hydroxyl or methoxy or monosubstituted by nitro, cyano,trifluoromethyl, amino, C₁ -C₄ -alkylamino or di-C₁ -C₄ -alkylamino or athienyl, naphthyl, benzothienyl or indenyl group which is unsubstitutedor substituted by fluorine, chlorine or nitro,and their salts withphysiologically tolerable acids.
 2. The compound of claim 1, whereinB isa 5- or 6-membered ring which can contain one double bond, R¹ is aphenyl group which is unsubstituted or monosubstituted by halogen atoms,R² is hydrogen, n is 2, and A is --NH--CO--N-phenyl.
 3. A method oftreating nervous disorders in a patient in need thereof which comprises:administering to the patient an effective amount of a compound of theformula I as defined in claim 1.